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Background: The blood-brain barrier (BBB) is part of the neurovascular unit (NVU) which plays a key role in maintaining homeostasis. However, its 3D structure is hardly known. The present study is aimed at imaging the BBB using tissue clearing and 3D imaging techniques in both human brain tissue and rat brain tissue. Methods: Both human and rat brain tissue were cleared using the CUBIC technique and imaged with either a confocal or two-photon microscope. Image stacks were reconstructed using Imaris. Results: Double staining with various antibodies targeting endothelial cells, basal membrane, pericytes of blood vessels, microglial cells, and the spatial relationship between astrocytes and blood vessels showed that endothelial cells do not evenly express CD31 and Glut1 transporter in the human brain. Astrocytes covered only a small portion of the vessels as shown by the overlap between GFAP-positive astrocytes and Collagen IV/CD31-positive endothelial cells as well as between GFAP-positive astrocytes and CD146-positive pericytes, leaving a big gap between their end feet. A similar structure was observed in the rat brain. Conclusions: The present study demonstrated the 3D structure of both the human and rat BBB, which is discrepant from the 2D one. Tissue clearing and 3D imaging are promising techniques to answer more questions about the real structure of biological specimens., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Aiwen Chen et al.)

Rationale: In the physiological states, the act of scratching protects the person from harmful substances, while in certain pathological conditions, the patient suffers from chronic itch, both physically and mentally. Chronic itch sufferers are more sensitive to mechanical stimuli, and mechanical hyperknesis relief is essential for chronic itch treatment. While neuropeptide Y-Y1 receptor (NPY-Y1R) system is known to play a crucial role in modulating mechanical itch in physiological conditions, it is elusive how they are altered during chronic itch. We hypothesize that the negative regulatory effect of Y1Rs on Tac2 neurons, the key neurons that transmit mechanical itch, declines during chronic itch. Methods: We combined transgenic mice, chemogenetic manipulation, immunofluorescence, rabies virus circuit tracing, and electrophysiology to investigate the plasticity of Y1Rs on Tac2 neurons during chronic itch. Results: We found that Tac2 neurons receive direct input from Npy neurons and that inhibition of Npy neurons induces activation of Tac2 neurons. Moreover, the expression of Y1Rs on Tac2 neurons is reduced, and the regulatory effect is also reduced during chronic itch. Conclusion: Our study clarifies the plasticity of Y1Rs on Tac2 neurons during chronic itch and further elucidates the mechanism by which NPY-Y1R system is responsible for modulating mechanical itch. We highlight Y1Rs as a promising therapeutic target for mechanical hyperknesis during chronic itch., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Re-examining the relationship between neuropeptide systems and neural circuits will help us to understand more intensively the critical role of neuropeptides in brain function as the neural circuits responsible for specific brain functions are gradually revealed. Gastrin-releasing peptide receptors (GRPRs) are Gαq-coupling neuropeptide receptors and widely distributed in the brain, including hippocampus, amygdala, hypothalamus, nucleus tractus solitarius (NTS), suprachiasmatic nucleus (SCN), paraventricular nucleus of the hypothalamus (PVN), preoptic area of the hypothalamus (POA), preBötzinger complex (preBötC), etc., implying the GRP/GRPR system is involved in modulating multiple brain functions. In this review, we focus on the functionality of GRPR neurons and the regulatory role of the GRP/GRPR system in memory and cognition, fear, depression and anxiety, circadian rhythms, contagious itch, gastric acid secretion, food intake, body temperature, and sighing behavior. It can be found that GRPR is usually centered on a certain brain nucleus or anatomical structure and modulates richer or more specific behaviors by connecting with additional different nuclei. In order to explain the regulatory mechanism of the GRP/GRPR system, more precise intervention methods are needed.

Myeloid differentiation factor 2 (MD2) is a co-receptor of a classical proinflammatory protein TLR4 whose activation leads to neuroinflammation. It is widely accepted that TLR4 is expressed on the cell surface of microglia and astrocytes, and MD2 is expected to be expressed by these cells as well. However, our previous study showed that neurons from certain nuclei also expressed MD2. Whether MD2 is expressed by other brain nuclei is still unknown. It is the aim of the present study to map the distribution of MD2-positive cells in the adult mouse brain. Immunohistochemical staining against MD2 was completed to localize MD2-positive cells in the mouse brain by comparing the location of positive cells with the mouse brain atlas. MD2-positive cells were found in the majority of mouse brain nuclei with clusters of cells in the olfactory bulb, cortices, the red nucleus, and cranial nuclei. Subcortical nuclei had heterogeneous staining of MD2 with more prominent cells in the basolateral and the central amygdaloid nuclei. The ventral pallidum and the diagonal bands had positive cells with similar density and shape. Prominent cells were present in thalamic nuclei which were nearly homogeneous and in reticular formation of the brainstem where cells were dispersed with similar density. The hypothalamus had fewer outstanding cells compared with the thalamus. The red nucleus, the substantia nigra, and the ventral tegmental area in the pretectum had outstanding cells. Motor cranial nuclei also had outstanding MD2-positive cells, whereas raphe, sensory cranial, and deep cerebellar nuclei had MD2-positive cells with moderate density. The presence of MD2 in these nuclei may suggest the involvement of MD2 in their corresponding physiological functions.

It is generally believed that higher dietary diversity is associated with better health status. The dietary diversity of individuals may change with age; however, evidence on the trajectory of change in the long-term and whether it is related to all-cause mortality is still scant. In this study, we used data from the China Health and Nutrition Survey (CHNS) collected in five follow-ups between 2004 and 2015 to explore the association between changes in dietary diversity scores (DDS) and all-cause mortality, as well as the dynamic change in DDS with age. In total, 6,737 subjects (aged between 30 and 60 at enrollment) were included in the analysis. Latent Class Trajectory Modeling (LCTM) was used to explore the different trajectories of DDS changes among participants. Four classes were identified: class 1 with the lowest average DDS (3.0) that showed a gradual decline during the follow-ups; class 2 with relatively low DDS (4.0) that experienced slight growth; class 3 with medium DDS (5.2) that also demonstrated similar growth rate to class 2; and class 4 with the highest DDS (6.7) maintained at a high level. Cox proportional hazards regression models were applied to investigate the association between the DDS trajectories and the risk of death. Only class 4, which was characterized by the highest and stable DDS, had significant reduced risk of all-cause mortality of 71.0% (hazard ratio [HR] : 0.29; 95% confidence interval [CI] : 0.10-0.83), 68% ( HR : 0.32; 95% CI : 0.11-0.89), and 66.0% ( HR : 0.34; 95% CI : 0.12-0.94), compared to classes 1, 2, and 3, respectively, while the first three classes showed no significant inter-class differences. When considering the average DDS during the study period, each point of increase in DDS corresponded to a 22% reduced risk of mortality ( HR : 0.78; 95% CI : 0.69-0.89). In summary, reaching and maintaining a higher DDS was associated with a decreased risk of all-cause mortality. Therefore, promoting diversified eating and increasing the accessibility of varieties of foods should be paid more attention from policymakers and be more emphasized in dietary guidelines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qu, Na, Yang, Yu, Chen and Zhao.)

Neural systems play important roles in the functions of acupuncture. But the unclear structure and mechanism of acupoints hinder acupuncture standardization and cause the acupuncture effects to be varying or even paradoxical. It has been broadly assumed that the efficacy of acupuncture depends on the biological signals triggered at acupoints and passed up along neural systems. However, as the first station to transmit such signals, the characters of the dorsal root ganglia (DRG) neurons innervating acupoints are still not well elucidated. We adopted Zusanli (ST36) as a representative acupoint and found most DRG neurons innervating ST36 acupoint are middle-size neurons with a single spike firing pattern. This suggests that proprioceptive neurons take on greater possibility than small size nociceptive neurons do to mediate the acupuncture signals. Moreover, we found that adenosine injected into ST36 acupoints could dose- and acupoint-dependently mimic the analgesic effect of acupuncture. However, adenosine could not elicit action potentials in the acutely isolated ST36 DRG neurons, but it inhibited I D currents and increased the areas of overshoots. Further, we found that 4 types of adenosine receptors were all expressed by ST36 DRG neurons, and A1, A2b, and A3 receptors were the principal reactors to adenosine. PERSPECTIVE: This study provides the major characteristics of ST36 DRG neurons, which will help to analyze the neural pathway of acupuncture signals. At the same time, these findings could provide a new possible therapy for pain relief, such as injecting adenosine or corresponding agonists into acupoints., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

When the body is under pathological stress (injury or disease), the status of associated acupoints changes, including decreased pain threshold. Such changes in acupoint from a "silent" to an "active" state are considered "acupoint sensitization," which has become an important indicator of acupoint selection. However, the mechanism of acupoint sensitization remains unclear. In this study, by retrograde tracing, morphological, chemogenetic, and behavioral methods, we found there are some dorsal root ganglion (DRG) neurons innervating the ST36 acupoint and ipsilateral hind paw (IHP) plantar simultaneously. Inhibition of these shared neurons induced analgesia in the complete Freund's adjuvant (CFA) pain model and obstruction of nociceptive sensation in normal mice, and elevated the mechanical pain threshold (MPT) of ST36 acupoint in the CFA model. Excitation of shared neurons induced pain and declined the MPT of ST36 acupoint. Furthermore, most of the shared DRG neurons express TRPV1, a marker of nociceptive neurons. These results indicate that the shared nociceptive DRG neurons participate in ST36 acupoint sensitization in CFA-induced chronic pain. This raised a neural mechanism of acupoint sensitization at the level of primary sensory transmission., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Liu, Chen, Dai, Zhao, Liu, Song, Xiong and Gao.)

The lateral habenula (LHb) is a tiny structure that acts as a hub, relaying signals from the limbic forebrain structures and basal ganglia to the brainstem modulatory area. Facilitated by updated knowledge and more precise manipulation of circuits, the progress in figuring out the neural circuits and functions of the LHb has increased dramatically over the past decade. Importantly, LHb is found to play an integrative role and has profound effects on a variety of behaviors associated with pain, including depression-like and anxiety-like behaviors, antireward or aversion, aggression, defensive behavior, and substance use disorder. Thus, LHb is a potential target for improving pain management and related disorders. In this review, we focused on the functions, related circuits, and neurotransmissions of the LHb in pain processing and related behaviors. A comprehensive understanding of the relationship between the LHb and pain will help to find new pain treatments.

To explore the potential mechanism of cancer patients appearing more vulnerable to SARS-CoV-2 infection and poor COVID-19 outcomes, we conducted an integrative bioinformatics analysis for SARS-CoV-2-required genes and host genes and variants related to SARS-CoV-2 susceptibility and COVID-19 severity. BLCA, HNSC, KIRC, KIRP, LGG, PCPG, PRAD, TGCT, and THCA patients carrying rs10774671-A (OAS1) genotype may be more likely to have poor COVID-19 outcomes relative to those who carry rs10774671-G, because individuals carrying rs10774671-A will have lower expression of OAS1, which serves as a protective factor against SARS-CoV-2 processes and poor COVID-19 outcomes. SARS-CoV-2-required genes were correlated with TME, immune infiltration, overall survival, and anti-cancer drug sensitivity. CHOL patients may have a higher risk of SARS-CoV-2 infection than healthy subjects. SARS-CoV-2-induced ACE2 and NPC1 elevation may have a negative influence on the immune responses of LUSC and CD8+T infiltration of LUAD, and negatively affect the sensitivity of anti-lung cancer drugs. LUSC and LUAD patients may have a varying degree of adverse outcomes if they are infected with SARS-CoV-2. miR-760 may target and inhibit ACE2 expression. Cancer patients appearing vulnerable to SARS-CoV-2 infection and having poor COVID-19 outcomes may be partly due to host genetic factors and dysregulation of SARS-CoV-2-required genes. OAS1, ACE2, and miR-760 could serve as the treatment and intervention targets for SARS-CoV-2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Liang, Zhang, Tian, Cong, Wu, Zhang, Gao, Li, Chen, Zhang, Dong, Wan, He, Dai, Li and Xiong.)

Xiaoxuming decoction (XXMD) has been traditionally used to manage stroke though debates on its clinical efficacy were present in the history. Till nowadays, it is still one of the most commonly used herbal recipes for stroke. One of the reasons is that a decent proportion of ischemic stroke patients still have residue symptoms even after thrombolysis with rt-PA or endovascular thrombectomy. Numerous clinical studies have shown that XXMD is an effective alternative therapy not only at the acute stage, but also at the chronic sequelae stage of ischemic stroke. Modern techniques have isolated groups of compounds from XXMD which have shown therapeutic effects, such as dilating blood vessels, inhibiting thrombosis, suppressing oxidative stress, attenuating nitric oxide induced damage, protecting the blood brain barrier and the neurovascular unit. However, which of the active compounds is responsible for its therapeutic effects is still unknown. Emerging studies have screened and tested these active compounds aiming to find individual compounds that can be used as drugs to treat stroke. The present study summarized both clinical evidence of XXMD in managing stroke and experimental evidence on its molecular mechanisms that have been reported recently using advanced techniques. A new perspective has also been discussed with an aim to provide new targets that can be used for screening active compounds from XXMD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Wang, Chen, Huang, Dong, Li, Gao, Wu, Li, Cong, Wan, Dai, He, Liang, Wang and Xiong.)

m6A RNA methylation regulators can regulate the growth, progression, and invasion of glioma cells by regulating their target genes, which provides a reliable support for the m6A regulator-target axes as the novel therapeutic targets and clinical prognostic signature in glioma. This study aimed to explore the role and prognostic value of m6A RNA methylation regulators and their targets. Expression profiles and clinicopathological data were obtained from the Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Clinical Proteome Tumor Analysis Consortium (CPTAC) datasets. Differential expression and correlation analyses were performed between normal and glioma tissues at mRNA and protein levels. Univariate Cox regression, survival, and Lasso Cox regression analyses were conducted to identify and establish the prognostic gene signature. Kaplan-Meier curve, multivariate Cox regression analysis, and ROC were utilized to evaluate the prognostic capacity of the prognostic gene signature. The correlation analysis, systematic bioinformatics analysis, and cell experiment were performed to further understand the potential underlying molecular mechanisms and drug sensitivity. Our results suggested that IGF2BP2, KIAA1429, METTL16, and METTL3, as well as 208 targets are involved in the occurrence of glioma, GBM, and LGG. YTHDF1 and 78 targets involved the occurrence of glioma and GBM, not LGG, among which 181 genes were associated with overall survival. From other findings and our cell experiment results, we demonstrated that METTL3 can activate Notch pathway and facilitate glioma occurrence through regulating its direct targets NOTCH3, DLL3, and HES1, and Notch pathway genes may serve as the potential treatment targets for glioma. Our study established and validated a seven-gene signature comprising METTL3, COL18A1, NASP, PHLPP2, TIMP1, U2AF2, and VEGFA, with a good capability for predicting glioma survival, which may guide therapeutic customization and clinical decision-making. These genes were identified to influence 81 anticancer drug responses, which further contributes to the early phase clinical trials of drug development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cong, Wu, Huang, Liang, Gao, Tian, Li, Chen, Wan, He, Dai, Li and Xiong.)

Idiopathic pulmonary fibrosis (IPF) is a progressive disease whose etiology remains unknown. The purpose of this study was to explore hub genes and pathways related to IPF development and prognosis. Multiple gene expression datasets were downloaded from the Gene Expression Omnibus database. Weighted correlation network analysis (WGCNA) was performed and differentially expressed genes (DEGs) identified to investigate Hub modules and genes correlated with IPF. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein-protein interaction (PPI) network analysis were performed on selected key genes. In the PPI network and cytoHubba plugin, 11 hub genes were identified, including ASPN, CDH2, COL1A1, COL1A2, COL3A1, COL14A1, CTSK, MMP1, MMP7, POSTN, and SPP1. Correlation between hub genes was displayed and validated. Expression levels of hub genes were verified using quantitative real-time PCR (qRT-PCR). Dysregulated expression of these genes and their crosstalk might impact the development of IPF through modulating IPF-related biological processes and signaling pathways. Among these genes, expression levels of COL1A1, COL3A1, CTSK, MMP1, MMP7, POSTN, and SPP1 were positively correlated with IPF prognosis. The present study provides further insights into individualized treatment and prognosis for IPF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wan, Huang, Cong, He, Chen, Wu, Dai, Li, Gao, Tian, Liang and Xiong.)

Background: The study of protein complexes and protein functional modules has become an important method to further understand the mechanism and organization of life activities. The clustering algorithms used to analyze the information contained in protein-protein interaction network are effective ways to explore the characteristics of protein functional modules., Results: This paper conducts an intensive study on the problems of low recognition efficiency and noise in the overlapping structure of protein functional modules, based on topological characteristics of PPI network. Developing a protein function module recognition method ECTG based on Topological Features and Gene expression data for Protein Complex Identification., Conclusions: The algorithm can effectively remove the noise data reflected by calculating the topological structure characteristic values in the PPI network through the similarity of gene expression patterns, and also properly use the information hidden in the gene expression data. The experimental results show that the ECTG algorithm can detect protein functional modules better.

The balance between exploration and exploitation is critical to the performance of a Meta-heuristic optimization method. At different stages, a proper tradeoff between exploration and exploitation can drive the search process towards better performance. This paper develops a multi-objective grasshopper optimization algorithm (MOGOA) with a new proposed framework called the Multi-group and Co-evolution Framework which can archive a fine balance between exploration and exploitation. For the purpose, a grouping mechanism and a co-evolution mechanism are designed and integrated into the framework for ameliorating the convergence and the diversity of multi-objective optimization solutions and keeping the exploration and exploitation of swarm intelligence algorithm in balance. The grouping mechanism is employed to improve the diversity of search agents for increasing coverage of search space. The co-evolution mechanism is used to improve the convergence to the true Pareto optimal front by the interaction of search agents. Quantitative and qualitative outcomes prove that the framework prominently ameliorate the convergence accuracy and convergence speed of MOGOA. The performance of the presented algorithm has been benchmarked by several standard test functions, such as CEC2009, ZDT and DTLZ. The diversity and convergence of the obtained multi-objective optimization solutions are quantitatively and qualitatively compared with the original MOGOA by using two performance indicators (GD and IGD). The results on test suits show that the diversity and convergence of the obtained solutions are significantly improved. On several test functions, some statistical indicators are more than doubled. The validity of the results has been verified by the Wilcoxon rank-sum test.

Objective: To observe the effects of conventional drug therapy combined with acupuncture and conventional drug therapy on the morbidity of post-stroke depression and recovery of neurological function in patients with acute stroke, and provide new ideas for prevention and treatment of post-stroke depression., Methods: Sixty patients were randomly divided into an observation group and a control group, 30 cases in each one.Conventional drug therapy was given in the control group;on the basis of conventional drug therapy,acupuncture was applied at Baihui (GV 20), Sishencong (EX-HN1), Neiguan (PC 6), Hegu (LI 4), Taixi (KI 3), etc. The treatment was given once every day, 6 times a week for 4 weeks in the two groups. The 24 Hamilton depression rating scale (HAMD), modified Edinburgh-Scandinavian stroke scale (MESSS) scores were recored before treatment, after 1 week of treatment, and after 4 weeks of treatment in the two groups,and the morbidity of post-stroke depression was compared between the two groups., Results: After 1 week of treatment, the HAMD scale scores of the two groups were higher than those before treatment (both P <0.05), and the MESSS scores were lower than those before treatment in the two groups (both P <0.05). After 4 weeks of treatment, the HAMD scale scores in the observation group were lower than that before treatment ( P <0.05), and significantly better than that in the control group ( P <0.01), but there was no significant difference in the control group before and after treatment ( P >0.05). The MESSS scores were lower than those after 1 week of treatment in the two groups (both P <0.05), and the score in the observation group was significantly lower than that in the control group ( P <0.01). After 4 weeks of treatment, the morbidity of post-stroke depression in the observation group was 23.3% (7/30), which was lower than 66.7% (20/30) in the control group ( P <0.05)., Conclusion: Early acupuncture intervention on stroke patients can not only promote the recovery of neurological function, but also reduce the morbidity of post-stroke depression effectively.

Objective: To observe the effect differences between herb-partition moxibustion and starch-partition moxibustion at navel for constipation with excess syndrome., Methods: Sixty patients were randomly assigned into an herb-partition moxibustion at navel group (herbal group) and a starch-partition moxibustion at navel group (starch group), 30 cases in each one. The acupoint was Shenque (CV 8) in the two groups. The treatment was given once a week and 4 times totally. Scores for constipation degree and quality of life (PAC-QOL) were observed before and after treatment and at follow-up; clinical effects were compared between the two groups as well., Results: After treatment, the scores of constipation degree and QOL were lower than those before treatment in the herbal group ( P <0.01, P <0.05), which were better than those of the starch group ( P <0.01, P <0.05). Good effects were achieved for heat constipation (84.6%), qi constipation (77.8%) and cold constipation (87.5%) in the herbal group, and the improvements of heat constipation and qi constipation were better than corresponding results in the starch group (both P <0.05). The effective rate of the herbal group was 83.3% (25/30), and it was better than 43.3% (13/30) of the starch group. The two scores at follow-up had no statistical significances compared with those after treatment in the herbal group (both P >0.05), but superior to ones of the starch group ( P <0.01, P <0.05); the effective rate of the herbal group was 86.6% (26/30), which was better than 50.0% (15/30) of the starch group ( P <0.01)., Conclusions: Herb-partition moxibustion at navel achieves better short-term and long-term effects than starch-partition for constipation with excess syndrome.